Identification of the major in vivo ABl-42-degrading catabolic-system in brain parenchyma.

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Accumulation of amyloid-pβ peptide (Ap) in brain triggers the pathological cascade leading to Alzheimer' s disease. To examine the mechanism of AB catabolism, we analysed the fate of multiply radio-labeled 3H/14C-Aβl-42 injected into rat hippocampus and identified neutral endopeptidase (s) similar or identical to neprilysin as the rate-1imiting peptidase using a panel of peptidase inhibitors. Chronic infusion of thiorphan, a specific inhibitor of neprilysin, into rat hippocampus caused accumulation of endogenous AB. To further identify the thiorphan-sensitive peptidase, we analysed ABl-42 catabolism by six recombinant thiorphan-sensitive peptidases in neutral endopeptidase family. Neprilysin degraded AB most rapidly and efficiently among them. Neprilysin-deficient mice showed significantly reduced ability to catabolize AB. We also observed a gene dosage-dependent clevation of the endogenous AB levels (-/- > +/- > +/+) in the mouse brains. The increase in the AB42 level in the neprilysin-deficient mouse brain was comparable to that in the mice carrying PSI mutation. Moreover, the regional Ap levels in wild-type mouse brain were in the order of hippocampus > cortex > striatum/thalamus > cerebellum and this tendency was markedly exaggerated in the neprilysin-deficient mice. In the experiments using aged mice, neprilysin activity and its protein content in hippocampus were reduced by 200% at 30 months-old ages, compared to 2 months-old ages. The neprilysin activity in cortex was also slightly but significantly reduced with aging, whereas those in other regions were not changed. These observations suggest that the neprilysin is the major AB-degrading enzyme in brain despite the molecular redundancy of the neprilysin family and that reduction of neprilysin activity particularly in the regions vulnerable to AB pathology will contribute to Alzheimer' s disease development by promoting AB deposition.